Aryl substituted-hydroxy substituted cyclohexenecarboxylic acids and esters

ABSTRACT

Hydroxyacids and hydroxyesters of the formula:   WHEREIN R is hydrogen or lower alkyl, R&#39;&#39; is lower alkyl and Ar is substituted aryl, are intermediates in the preparation of 2lower alkyl-3-lower alkyl-4-aryl-cyclohexenecarboxylic acids and esters which are active agents for the suppression of animal reproduction.

United States Patent m1 Karmas Oct. 9, 1973 ARYL SUBSTITUTED-HYDROXY SUBSTITUTED CYCLOHEXENECARBOXYLIC ACIDS AND I ESTERS [75] Inventor:

[73] Assignee: Ortho Pharmaceutical Corporation,

Raritan, NJ.

221 Filed: Sept. 23, 1970 21 Appl. No.2 74,859

Related US. Application Data [62] Division of Ser. No. 662,295, Aug. 22, 1967, Pat. No.

George Karmas, Bound Brook, NJ.

[52] US. Cl 260/340.5, 260/327, 260/34S.7, 260/488, 260/414, 260/516, 260/518, 260/519, 260/520, 424/282 [51] Int. Cl C07d 13/10 [58] Field of Search 260/340.5

[56] References Cited UNITED STATES PATENTS Mebane 260/326.5

OTHER PUBLICATIONS Nathan, et al., Journ. Amer. Chem. 500., Vol 78 (1956) pp. 6163-6166.

Primary ExaminerAlex Mazel Assistant'ExaminerJames H. Tumipseed Attorney-Alexander T. Kardos [57] ABSTRACT, Hydroxyacids and hydroxyesters of the formula:

OH AI QCOOR 1 Claim, No Drawings 1 ARYL SUBSTlTUTED-HYDROXY SUBSTITUTED CYCLOHEXENECARBOXYLIC ACIDS AND ESTERS This is a division of application Ser. No. 662,295; filed Aug. 22, 1967 now US. Pat. No. 3,567,770.

The compounds of the present invention are of the formula:

wherein R is hydrogen or lower alkyl of up to eight carbon atoms, R is lower alkyl of up to six carbon atoms and Ar is wherein R, is hydrogen, hydroxy, lower alkoxy of up to four carbon atoms, lower acyloxy of up to five carbon atoms or tetrahydropyranyl-Z-oxy, R is hydrogen, hydroxy, lower alkyl of up to four carbon atoms, lower alkoxy of up to four carbon atoms, lower acyloxy of up to five carbon atoms, chlorine, tetrahydropyranyl-2- oxy or trifluoro-methyl and R is hydrogen, hydroxy,

lower alkyl of up to four carbon atoms, lower acyloxy of up to five carbon atoms, diethylaminoethoxy, thiomethyl, trifluoromethyl, dimethylamino or 'tetrahydropyranyl-2-oxy, and wherein at least I and not more than 2 of R,, R and R is hydrogen; 3,4- methylenedioxyphenyl, a-naphthyl or B-naphthyl.

The compounds of the present invention are prepared by the saponification of their corresponding lactones or by the reaction of an aryl Grignard reagent or an aryl lithium compound and a 2-lower alkyl-3-lower' alkyl-4-ketocyclohexanecarboxylic acid. The preparation of the lactones is disclosed in my copending application Ser. No. 662,282 filed Aug. 22, 1967, now abandoned. The utility of the 2-lower alkyl-3-lower alkyl-4- aryl-cyclohexenecarboxylic acids and esters prepared from the compounds of the present invention is fully described in my copending application Ser. No. 662,311 filed Aug. 22,1967, now abandoned.

The preparation of the compounds ofthe invention is illustrated by the following reaction schemes:

The compounds of the invention are used to prepare the final 2-lower alkyl-3-low'er alkyl-4-arylcyclohexenecarboxylic acids and esters according to the following reaction scheme:

anecarboxylic acid Typical lactone starting materials for the compounds of the present invention are the lactones of:

2-methyl-3-ethyl-4-hydroxy-4-(m-anisyl)cyclohex-' anecarboxylic acid, 2,3-di'methyl-4-hydroxy-4-(m-anisyl)cyclohexanecarboxylic acid,

2,3-diethyl-4-hydroxy-4-(m-anisyl)cyclohexanecarboxylic acid,

2-methyl-3-propyl-4-hydroxy-4-(m-anisyl)cyclohexanecarboxylic acid,

2-propyl-3-butyl-4-hydroxy-4-(m-anisyl)cyclohexanecarboxylic acid,

2,3-dimethyl-4-hydroxy-4-(mtetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid,

2,3-diethyl-4-hydroxy 4-(mtetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid,

2-ethyl-3-butyl-4-hydroxy-4-( 3,4- methylenedioxyphenyl)cyclohexanecarboxylic acid,

2,3-diethyl-4-hydroxy-4-(ptrifluoromethylphenyl)cyclohexanecarboxylic acid,

2,3-dibutyl-4-hydroxy-4-(mtrifluoromethylphenyl)cyclohexanecarboxylic acid,

2-methyl-3-propyl-4-hydroxy-4-(o-methoxy-pacetoxyphenyl)cyclohexanecarboxylic acid,

2-methyl-3-butyl-4-hydroxy-4-(o,pdiacetoxyphenyl)cyclohexanecarboxylic acid,

The following examples illustrate the preparation of the compounds of the invention.

EXAMPLE I 2-Methyl-3-ethyl-4-hydroxy-4-(m-anisyl)cyclohex- A mixture of 10.0 g. of the lactone of 2-methyl-3- ethyl-4-hydroxy-4-(m-anisyl)cyclohexanecarboxylic acid, 10.0 g. of sodium hydroxide, 100 ml. of methanol and.l00 ml. of water is stirred and refluxed for two hours and is then diluted with 250 ml. of waterand evaporated to remove the methanol. The solution is acidified with dilute hydrochloric acid, and is extracted with ether. The ether solution is rapidly washed with water, driedover anhydrous magnesium sulfate and filtered. The residue is recrystallized from ether to afford 2-methyl-3-ethyl-4-hydroxy-4-(m-anisyl)cyclohexanecarboxylic acid; m.p. 203-204C. )txmaxz 2.83, 5.87 and 5.94 (split), 7.78, 8.03, 10.23, 12.80, 14.27 p. (KBr) NMR (pyr.): 0.63, 0.75, 0.87; 1.46, 1.57; 2.96

.Following the procedure of Example I, but starting with the appropriate lactone, there are prepared:

C. U.V. max. (KBr) Example Compound formed 11 2-methyl-3ethyl4- 187-188 2.82, 5.87 and 5.97 (split),

hydroxy4-(o-anlsyD- 7.74, 8.10, 9.67, 13.20;. cyltohexanecarboxyllc III 2-methyl-3-ethyl-4- 189-190 2.83, 5.90, 7.99, 10.37,

I hydroxyt-(p-thio- 11.00, 12.29

anisylycyclohexanecarbozyllc acid.

M.P., Example Compound formed C. U.V. max. (KBr) IV 2-methyl-3-ethyl-4- 201-202 2.82, 5.90, 8.10, 10.32,

' 'hydroxy-4-(p-tolyD- 12.27, 14.10 1.

cyicohexanecarboxylic ac V 2-methyl-3 ethyl-4- 154-155 2 82, 5.89, 8.01, 8 40, 1 hydroxy-4-(m-tolyl)- 9 60, 12.78, 13 62, 1

ey rgohexanecarboxylic VI 2-rnethyI-3-ethyl-4- 200-201 2.83, 5.87 and 5.98 (split),

hydroxy-4-(p-tr1fluoro- 7.50, 8.92, 9.30, 11.81, methylphenyDcyclo- 12.0 p. hexanecarboxylie acid.

VII 2-methy1-3-ethyl-4- 160-170 2.85, 5.83 and 5.97 (split),

hydroxy-4-(m- 7.50, 8 60, 8.92, 12 48, trlfluoromethyl- 14.22, 14 9 1., phenyDcyclohexanecarboxylic acid.

VIII 2-methyl-3ethyl4- 196-197 2 82, 88 and 5.94 (split),

hydroxy-4-(3A- 8 9 60, 10.63, 12 35;: methylenedioxyphenyl)cyclohexanecarboxylic acid.

IX 2-methyl3-ethyl-4- 177-178 2.82, 5.87 and 5.95 (split),

hydroxy-4-(a- 7.70, 10.13, 11.60, .4 naphthyD-cyclo- 12.89 1. hexanecarbox 11c acid.

X. 2-methyl-3-ethy -4- 216-217 2.85, 5.90, 8.00, 8 58, 1167 hydroxy-i-(B- 12.20 ,13.33 1. naphthyll-cyclo hexanecarboxyllc acid.

XI 2-methyl-3-ethyl-4- 164466 2.83, 5.88, 8.02, 9.62, 10.10,

hydro! -4-(a- 11.79, .15, 14.33 1. thlenyl -cycl0- hexanecarboxylic acid.

XII 2-methyl-3-ethy1-4- 142-143 2.88, 5. 8 23, 10.14,

hydroxyA-benzyleyclo- 11.51, 13.03, 14.1 hexanecarboxylic acid.

XIII 2-methy1-3-pr0py1-4-(p- 196-197 2.84, 5.90, 7.99, 9.57, 11.90

an1syl)cycl0hexane- 12.35 1.

carboxyllc acid.

EXAMPLE XIV 2-Methyl-3-ethyl-4-hydroxy-4-(mtetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid A mixture of 10.0 g. of the lactone of 2-methyl-3- ethyl-4-hydroxy-4- (m-tetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid, 10.0 g. of sodium hydroxide,

100 ml. of methanol and 100 ml. of water is stirred and refluxed for 2 hours. It is then diluted with 250 ml. of water and evaporated to remove methanol. The insoluble oily material is removed by extraction with ether and is discarded, 200 ml. of methylene chloride is added to the solution and the mixture is stirred and is maintained at 0-5C. while making the mixture'barely acidic with cold dilute hydrochloric acid. The methylene chloride phase is separated, washed twice with brine, dried over anhydrous magnesium sulfate and evaporated to a residue. The residue is recrystallized from ether to afford 2-methyl-3-ethyl-4-hydroxy-4-(mtetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid, m.p. 149151C.

)tkmax: 2.83, 5.88, 8.02, 8.98, 9.61, 10.34, 10.92 11..

(KBr) NMR (pyr.): 0.62, 0.73, 0.85; 1.46, 1,58; 2.95

Following the procedure of Example XIV, there are prepared:

EXAMPLE xv 2-Methyl-3-ethyl-4-hydroxy-4 (otetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid; m.p. l641 66C.

'Mtmax: 2.88, 5.87, 8.13, 10.24, 10.85, 11.52, 13.28 1.1..

(KBr) NMR (pl n): 0.67, 0.79, 0.90; 1.47, 1.58; 2.97

EXAMPLE XVI 2-Methyl-3-ethyl-4-hydroxy-4-( o-methoxy-ptetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid, m.p. 118-l 30C.

Mmax: 2.86, 5.87, 8.31, 9.62, 10.10, 11.04, 11.92 1.. (KBr) 4 NMR (pyr.): 0.65, 0.76, 0.88; 1.46, 1.57, 2.93 NMR c1501., 0.67, 0.78, 0.89; 1.02, 1.13; 1.82, 2.57

EXAMPLE XVII 2-Methyl-3-ethyl-4-hydroxy-(o,p-bistetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid, m.p. l0O-108C.

,Mtmax: 2.88, 5.87, 7.99, 9.61, 9.97, 10.38, 10.95,

11.85 ,1. (KBr) NMR (pyr): 0.73, 0.85, 0.96; 1.52, 1.63; 2.98 Calcd.

for c,,11,,o c, 67.51; 11, 8.28

Found 1 c, 67.00; 11, 8.33

EXAMPLE XVIII ether. The ether solution is washed twice with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is recrystallized from ether-methylene chloride to afford 2-methyl-3-ethyl-4- hydroxy-4-(m-hydroxyphenyl)cyclohexanecarboxylic acid, m.p. 211-213C.

)tltmaxz 2.96, 3.15, 5.78, 7.50, 9.60, 13:31, 14.23 1.. (KBr) NMR (pyr.): 0.63, 0.74, 0.85; 1.45, 1.57; 2.92

EXAMPLE XIX 2-Methyl-3-ethyl-4hydroxy -4-(o-hydroxyphenyl)- cyclohexanecarboxylic acid Following the procedure of Example XVIII, but starting with 2-methyl-3-ethyl-4-hydroxy-4-(otetrahydropyranyloxyphenyl)-cyclohexanecarboxylic aicd (as prepared in Example XV), there is afforded 2-methyl-3-ethyl-4-hydroxy-4-(o-hydroxyphenyl)cyclohexanecarboxylic acid, m.p. 190-191C. )Otmax: 2.82, 3.04, 5.90, 8.06, 10.40, 10.69, 10.92, 13.23 a. (KBr) NMR (pyr.): 0.67, 0.78, 0.89; 1.42, 1.53; 2.96

EXAMPLE XX 2-Methyl-3-ethyl-4-hydroxy-4-(o,p-dihydroxyphenyl)- cyclohexanecarboxylic acid Following the procedure of Example XVIII, but starting with 2-methyl-3-ethyl-4-hydroxy-4-(o,p-bistetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid (as prepared in Example XVII), there is afforded 2-methyl-3-ethyl-4-hydroxy-4-(o,pdihydroxyphenyl)cyclohexanecarboxylic l6917lC.

Ahmax: 2.85, 2.95, 3.12, 5.90, 8.62, 8.89, 10.21, 11.81, 12.10,12.42 1.1..(KBr) NMR (Pyr.): 0.72, 0.82, 0.93; 1.40, 1.52; 2.92

EXAMPLE XXI acid, m.p.

2-Methyl-3-ethyl-4-hydroxy-4-(o-methoxy-phydroxyphenyl cyclohex'anecarboxylic acid Following the procedure of Example XVIII, but starting with 2-methyl-3-ethyl-4-hydroxy-4-(o-methoxy p- EXAMPLE XXII 2-Methyl-3-ethyl-4-hydroxy-4-(m-acetoxyphenyl)cy clohexanecarboxylic acid To a solution of 2.0 g. of 2-methyl-3-ethyl-4-hydroxy- 4-(m-hydroxyphenyl)cyclohexanecarboxylic acid (as prepared in Example XVIII), in 25 ml. of pyridine is added with stirring 3 ml. of acetic anhydride. The solu-- tion is maintained at 25C. for 20 hours and is then hydrolyzed with ice and water. The oily products are extracted with ether. The ether solution is washed with cold dilute hydrochloric acid to remove pyridine and is then extracted with three cold portions of 7 percent aqueous potassium carbonate with each successive carbonate wash being immediately acidified with dilute hydrochloric acid. A tacky precipitate from the carbonate solutions is extracted with ether and the combined ether solution is dried and evaporated at 25C. The residue is recrystallized from ether to afford'2- methyl-3-ethyl-4-hydroxy-4-(m-acetoxyphenyl)cyclohexanecarboxylic acid, m.p. 172-173C.

' Mtmax: 2.83, 5.68, 8.30, 9.63, 10.71, 12.73 1!.(KB1) NMR (pyr.): 0.61, 0.71, 0.82; 1.44, 1.55; 2.94

EXAMPLE XXIII 2-Methyl-3-ethyl-4-hydroxy-4-(o-acetoxyphenyl)- cyclohexanecarboxylic acid Following the procedure of Example XXII, but starting with 2-methyl-3-ethyl-4-hydroxy-4-(ohydroxyphenyl)cyclohexanecarboxylic acid (as prepared in Example XIX), there is afforded 2-methyl-3- ethyl-4-hydroxy-4-(o-acetoxyphenyl)cyclohexanecarboxylic acid, m.p. l32l33C. Mtmax: 2.82, 5.72, 5.89, 8.20, 8.48, 13.09 1.1.(KB1') NMR (pyr.): 0.68, 0.80, 0.91; 1.43, 1.55; 2.96

EXAMPLE XXIV 2-Methyl-3-ethy1-4-hydroxy-4-(o,p-diacetoxyphenyl)- cyclohexanecarboxylic acid Following the procedure of Example XXII, but starting with Z-methyl-3-ethyl-4-hydroxy 4-(o,pdihydroxyphenyl)cyclohexanecarboxylic acid (as prepared in Example XX), there is afforded 2-methyl-3- ethyl-'4-hydroxy-4-(o,p-diacetoxyphenyl)cyclohexanecarboxylic acid, m.p. 110-112C. Mmax: 2.85, 5.68, 8.10-8.40, 9.80, 10.87 p (KBr) NMR (CDCL 0.64, 0.75, 0.86; 0.99, 1.10; 1.89, 2.59

OH Q l CH3 O2 CzHa CH;

I, II,

Compounds 1 and II are mixtures of the A and A isomers.

EXAMPLE XXV 2-Methyl-3-ethyl-4-hydroxy-4-(m-chlorophenyly cyclohexanecarboxylic acid The Grignard reagent from 0.32 mole of mchlorobromo-benzene, prepared in a mixture of ether and tetrahydrofuran, is stirred at 40 and to it is added 0.1 mole of 2-methy1-3-ethyl-4-ketocyclohexanecarboxylic acid in 40 m1. of tetrahydrofuran. This reaction mixture is stirred vigorously and heated at the reflux temperature for 2 hours and then it is cooled in ice and hydrolyzed with 400 ml. of saturated aqueous ammonium acetate. After filtration to remove magnesium, the layers are separated and the organic phase is dried and evaporated to a tacky, semi-crystalline residue.

7 Recyrstallization from ether or nitromethane affords The o-acetoxyphenyl-hydroxy acids prepared ac-' cording to Examples XXIII and XXIV are unstable and begin to decompose after a few days at 25C. They are fully decomposed within 2 to 3 weeks at 25C. The decomposition follows the route:

9.0 g. of 2-methy1-3-ethy1 4-hydroxy-4-(mchlorophenyl)-cyclohexanecarboxylic acid, m.p. l66-169C.

Mmax: 2.83, 5.89, 8.01, 12.77, 13.79 1.1. (KBr) NMR (pyr.): 0.59, 0.70, 0.80; 1.40, 1.52; 2.92

The alkyl esters of the compounds of the invention are prepared by treatment of metal salts of the hydroxyacids with an appropriate dialkyl sulfate.

EXAMPLE XXVI Methyl 2-methyl-3-ethyl-4-hydroxy-4-phenylcyclohexanecarboxylate A solution of 4.0 g. of 2-methyl-3-ethyl-4-hydroxy-4- phenylcyclohexanecarboxylic acid and 1.5 g. of sodium hydroxide in 40 ml. of methanol and 150 ml. of dimethylformamide is evaporated under vacuum to a volume of ml. The resulting suspension is stirred and cooled to 15C. 3.5 ml. of dimethyl sulfate is added and the mixture is stirred at 25C. for thirty minutes and is then evaporated under vacuum to remove most of the dimethylformamide. The residue of about 15-20 ml. is shaken with ether and water, and the ether solution is washed with cold 5 percent sodium hydroxide, fol- .lowed by four portions of water. The ether solution is dried and evaporated to a residue. The residue is recrystallized from hexane to afford methyl 2-methyl-3- ethy1-4-hydroxy-4-phenylcyclohexanecarboxylate, m.p. 112-113C. Mmax: 2.87, 5.79, 8.21, 8.55, 13.29, 14.30 p. (KBr) Calcd. for C I-1 0;, C, 73.88; H, 8.75

Found C, 74.00; H, 8.76

EXAMPLE XXVII Methyl 2-rnethyl-3-ethyl-4-hydroxy-4-(ptrifluoromethylphenyl)cyclohexanecarboxylate Following the procedure of Example XXVI, but starting with 2-methy1-3-ethyl-4-hydroxy-4-(ptrifluoromethylphenyl)cyclohexanecarboxylic acid, there is afforded methyl 2-methyl-3-ethy1-4-hydroxy-4- (p-trifluorom ethylphenyl )cyclohexanecarboxylate m.p. ll2-l 13C.

' Mtmaxz 2.89, 5.88, 7.49, 7.82, 8.6l, 8.90, 9.29, 9.84,

11.81, 12.04 pt. (KBr) Calcd. for C H O F C, 62.79; H, 6.73

Found 1 C, 63.07; H, 6.73

EXAMPLE XXVIII ethyl Z-methyl-3-ethyl-4-hydroxy-4-benzylcyclohexanecarboxylate,

propyl 2-methyl-3-propyl-4-hydroxy-4-benzylcyclohexanecarboxylate,

ethyl 2-ethyl-3-methyl-4-hydroxy-4-benzylcyclohexanecarboxylate, v

ethyl 2,3-dimethyl-4-hydroxy-4-benzylcyclohexanecarboxylate,

ethyl 2,3-diethyl-4-hydroxy-4-benzylcyclohexanecarboxylate,

butyl 2-methyl-3-ethyl-4-hydroxy-4-benzylcyclohexanecarboxylate,

butyl 2-ethyl-3-butyl-4-hydroxy-4-benzylcyclohexanecarboxylate,

butyl 2-methyl-3-ethyl-4-hydroxy-4-(m-tolyl)cyclohexanecarboxylate, and

butyl 2-methyl-3-propyl-4-hydroxy-4-(m-tolyl)cyclohexanecarboxylate. I

What is claimed is:

1. 2-Methyl-3-ethyl-4-hydroxy-4-(3,4- methylenedioxyphenyl)cyclohexanecarboxylic acid. 

